Abstract

We describe a three-generation Norwegian family with a novel X-linked intellectual disability (XLID) syndrome characterized by subtle facial dysmorphism, autism and severe feeding problems. By exome sequencing we detected a rare missense variant (c.1067A>G, p.(Tyr356Cys)) in the RLIM gene, in two affected male second cousins. Sanger sequencing confirmed the presence of the variant in the four affected males (none of whom were siblings) and in three mothers available for testing. The variant was not present in 100 normal Norwegian controls, has not been reported in variant databases and is deleterious according to in silico prediction tools. The clinical phenotype and the variant co-segregate, yielding a LOD score of 3.0 for linkage to the shared region (36.09 Mb), which contains 242 genes. No other shared rare variants on the X chromosome were detected in the two affected exome-sequenced individuals, and all female carriers had an extremely skewed X-chromosome inactivation pattern. RLIM encodes RING zinc finger protein 12 (RNF12), an ubiquitin ligase that is essential for X inactivation in mice and that acts as a co-regulator of a range of transcription factors, particularly those containing a LIM homeodomain. Tyrosine in position 356 in RNF12 is located within a highly conserved domain essential for binding such transcription factors. Expression of RNF12 is widespread during embryogenesis, and is particularly high in the outer layers of the cerebral cortex. Functional studies are needed to prove a definite causal relationship between the variant and the phenotype. Subsequent reports may confirm a role for RLIM variants in patients with XLID.

Overview of the pedigree. Black symbols denote affected individuals and symbols with a dot denote carriers. X-inactivation patterns (f.ex. 100:0) are shown underneath the identifier for individuals II:3, II:4, II:5, III:1, III:2 and III:4; for individuals II-5 and III-2 the analysis was performed twice. All individuals except I:1 and I:2 (*) were genotyped for the variant c.1067A>G in RLIM.

Alignment of the LIM binding domain of RLIM. The position of the variant c.1067A>G is marked with a yellow box, and is predicted to result in the substitution of the amino acid tyrosine in position 356 by cysteine: p.(Tyr356Cys) or p.(Y356C). Tyr (Y) 356 is located in a highly conserved region of the RNF12 protein, essential for binding to LIM-containing proteins, as shown by Ostendorff et al.